NSC 652287D showed potent differential growth inhibitory activity against selected renal ovarian, colon and lung human tumor cell lines in the NCI primary in vitro anticancer drug screen. The primary objectives of the project are to characterize the disposition of the compound in mice in order to define a dose route and schedule which can be used for in vivo efficacy studies, and to determine if plasma concentrations of the compound shown to be effective in vitro (50 to 100 nM) can be maintained for 3 to 6 hours in the dog without toxic effects. Plasma concentration- time profiles exhibited triexponential behavior following IV injection of 25, 50 and 100 mg/kg in mice. The initial phase had a rapid half-life (1-2 minutes) and accounted for 99% of the area under the curve. The terminal half-life varied from 2 to 3 hours. The plasma clearance decreased with increasing dose, indicating non-linear kinetics over this dose range. Lower doses will be tried to further define the kinetics in the mouse. Oral studies conducted in mice at a dose of 400 mg/kg, indicated very poor oral bioavailability (1%) of the compound). As was the case in the mouse, plasma concentration-time profile exhibited triexponential behavior with an initial half-life of 1.1 minute and a terminal half-life of 3 hours. Plasma clearance was very rapid (368 ml/min/kg). The initial (distribution) phase accounted for 87% of the area under the concentration-time profile. This dose was lethal, the dog succumbing to pulmonary toxicity typified by interstitial pneumonia and Type II cell hyperplasia. In an attempt to minimize the peak plasma concentrations, the same dose was given to another dog as a 1 hour continuous IV infusion. Plasma concentrations during the infusion were approximately 1-2 microM, which declined rapidly following the infusion. The plasma clearance was 70 ml/min/kg, far lower than the initial dog. This dose regimen was also lethal. In a further attempt to define concentrations of the compound which will be tolerated in the dog, a dose of 0.2 mg/kg was given to 2 dogs as a 1 hour IV infusion. The steady state plasma concentrations were 6 and 320 nM respectively. Plasma clearances were 1800 and 34 ml/min/kg. No evidence of toxicity was observed in either dog. Additional studies to define tolerable levels of the compound in the dog will continue as will studies into the mechanism of pulmonary toxicity.